management of hypertension in diabetes · 49 year old male diagnosed with hypertension 6 months ago...
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Nεώτερες κατευθυντήριες οδηγίες για την αρτηριακή υπέρταση μέσα από
περιστατικά
Κώστας ΤσιούφηςΚαθηγητής Καρδιολογίας ΕΚΠΑPresident of European Society of Hypertension (ESH)(2017-19)Πρόεδρος ΕΚΕ (2017-18)
Δήλωση σύγκρουσης συμφερόντων
✓Εχω λάβει υποστήριξη συμμετοχής σε συνέδρια ή ερευνητική υποστήριξη ή τιμητική
αμοιβή ομιλίας από Medtronic, St. Jude Medical, Bayer, Novartis, Astra-Zeneca,
Boehringer In, Pfizer, Chiesi, Pharmanel, Sanofi, Vianex, Win-Medica, Elpen
✓49 year old male
✓Diagnosed with hypertension 6 months ago
✓Obese with a BMI:37.2 kg/m2, Waist =112 cm
✓Hx: hyperlipidemia, Office BP:157/95 mmHg, (3 readings, automated
device, appropriate cuff, both arms, sitting and standing position)
✓Heart rate : 68 bpm
• Home BP readings : 150/90-95 mmHg
• Physical examination : unremarkable
The Story
✓No drugs for hypertension
✓Other drugs:
• For high cholesterol: Atorvastatin.
• For high uric acid: Allopurinol
Therapy
✓ HCT: 44.1%, WBC: 10,3 , PLT: 341
✓ HbA1C=6.3%, Serum K+=4.9mEq/l
✓ eGFR: 68 ml/min/1,73m2, ACR: 40 mg/g
✓ ECG and echo : normal
➢Retinal: grade I
➢High salt intake
Laboratory and TOD data
Classification of blood pressure
Recommendation Class Level
It is recommended that BP be classified as
optimal, normal, high-normal, or grades 1–3
hypertension, according to office BP.
I C
Classification of office BP and definitions of hypertension grade
Category Systolic (mmHg) Diastolic (mmHg)
Optimal < 120 and < 80
Normal 120–129 and/or 80–84
High normal 130–139 and/or 85–89
Grade 1 hypertension 140–159 and/or 90–99
Grade 2 hypertension 160–179 and/or 100–109
Grade 3 hypertension ≥ 180 and/or ≥ 110
Isolated systolic hypertension ≥ 140 and < 90
Categories of BP in Adults*
*Individuals with SBP and DBP in 2 categories should be
designated to the higher BP category.
BP indicates blood pressure (based on an average of ≥2
careful readings obtained on ≥2 occasions, as detailed in
DBP, diastolic blood pressure; and SBP systolic blood
pressure.
BP Category SBP DBP
Normal <120 mm Hg and <80 mm Hg
Elevated 120–129 mm Hg
and <80 mm Hg
Hypertension
Stage 1 130–139 mm Hg
or 80–89 mm Hg
Stage 2 ≥140 mm Hg or ≥90 mm Hg
Definitions of hypertension according to office, ambulatory, and home BP levels
Category Systolic (mmHg) Diastolic (mmHg)
Office BP ≥ 140 and/or ≥ 90
Ambulatory BP
Daytime (or awake) mean ≥ 135 and/or ≥ 85
Night-time (or asleep) mean ≥ 120 and/or ≥ 70
24-h mean ≥ 130 and/or ≥ 80
Home BP mean ≥ 135 and/or ≥ 85
Screening and diagnosis of hypertension
Out-of-Office and Self-Monitoring of BP
COR LOERecommendation for Out-of-Office and Self-Monitoring
of BP
I ASR
Out-of-office BP measurements are recommended to confirm the diagnosis of hypertension and for titration of BP-lowering medication, in conjunction with telehealth counseling or clinical interventions.
SR indicates systematic review.
Case Baseline ABPM
Clinical indications for HBPM or ABPM
Conditions in which white-coat hypertension is more common, for example:
• Grade I hypertension on office BP measurement
• Marked office BP elevation without HMOD
Conditions in which masked hypertension is more common, for example:
• High-normal office BP
• Normal office BP in individuals with HMOD or at high total CV risk
Postural and post-prandial hypotension in untreated and treated patients
Evaluation of resistant hypertension
Evaluation of BP control, especially in treated higher-risk patients
Exaggerated BP response to exercise
When there is considerable variability in the office BP
Evaluating symptoms consistent with hypotension during treatment
Specific indications for ABPM rather than HBPM:
• Assessment of nocturnal BP values and dipping status (e.g. suspicion of nocturnal hypertension, such as in sleep apnoea, CKD, diabetes, endocrine hypertension, or autonomic dysfunction)
ABP/Home BP, Documented advantages over Office BP
• Greater reproducibility (Trazzi, JH 1991, 9, 115)
• Little/No placebo effect (Mancia, AJH 1995, 8, 311)
• Little/No white coat effect (Parati, Hypertension 1985, 7, 597)
• Better prediction of CV outcomes
➢ Steeper 24h BP/outcome relationship
➢ Outcome prediction survives adjustment for office BP
Scientific quality of office vs ABP/Home BP prognostic studies
• In office BP-based long term prognostic studies serial office BP values (“usual” BP) are
available while in ABP/Home BP long term prognostic studies only one initial value is
available
• This is true in studies on both untreated and treated patient cohorts
• Are the single ABP/Home BP values reproducible and representative of the prevailing
values during the FU, particularly in treated patients?
▪ What is the incremental benefit for CV risk prediction of the addition of out-of-office BP (HBPM or
ABPM) to office BP measurements?
▪ What are the optimal treatment targets according to HBPM and ABPM?
Routine use of out-of-office BP or
improvement of the quality of office BP measurements?
Johnson KC et al. Hypertension. 2017;71:848-857.
Average post-randomization Systolic BPs and medications, controlling for subject, visit and clinical site
Always Alone Never Alone Alone for Rest Alone for BP Measurement
Mean (95%CI) Mean (95%CI) Mean (95%CI) Mean (95%CI)
Systolic BP, mm HG
Intensive Participants 121.4 (120.7, 122.0) * 121.0(120.2,121.8)* 122.2 (121.3, 123.1)* 120.6 (119.1, 122.2)*
Standard Participants 134.4 (133.8, 135.1)* 134.4 (133.6, 135.1)* 134.7 (133.8, 135.6) 135.4 (133.8, 136.9)*
Difference 13.1 (12.6, 13.5)* 13.3 (12.7, 13.9) * 12.5 (11.9, 13.2)* 14.7 (13.5, 15.9)
Number of Medications
Intensive Participants 2.7 (2.7, 2.8)* 2.8 (2.7, 2.9)* 2.7 (2.6, 2.8)* 2.5 (2.4, 2.7)*
Standard Participants 1.8 (1.8, 1.9)* 1.9 (1.8, 2.0)* 1.8 (1.7, 1.9)* 1.8 (1.6, 1.9)*
Difference 0.9 (0.8, 1.0)* 0.9(0.9, 1.0)* 0.9 (0.8, 1.0)* 0.8 (0.6, 0.9)*
*P>0.05 for pairs of BP measurement techniques
SPRINT Attended vs. Unattended BP Measurement Survey
To fully realize benefits and minimize risks associated with SPRINT intensive treatment
algorithm
Use of validated automated BP device,
Staff training to allow for a quiet rest period,
Proper positioning, use of proper cuff size, and
Averaging readings
seemed more important than whether BP measurement was attended or unattended.
Johnson KC et al. Hypertension. 2017;71:848-857
Identification and reversal of Lifestyle factors contributing to uncontrolled HTN
◼ Salt consumption
◼ Obesity
There is very limited evidence for long-term effects of lifestyle interventionson BP and health outcomes but yet, there is no evidence for harmful effects
Patnode, JAMA 2017
The benefit is greatest whenmultiple lifestyle interventions are incorporated simultaneously
History and physical examination
Quantification of Daytime sleepiness
Objective methods MULTIPLE SLEEP LATENCY TEST (MSLT)
Subjective methods EPWORTH SLEEPINESS SCALE
Diagnosis of Sleep apnea syndrome
Quantification of sleep related breathing disorders (Polysomnography)
Sleep disorders are
common, serious, treatable and
underdiagnosed
CPAP in OSA-related HTN
◼Most interventional trials in OSA and subsequent meta-analyses have indicated that CPAP has only a modest
effect on BP levels
◼ Tsioufis et al, J Hypertension 2010
Randomized controlled study
In patients with RHTN and OSA, CPAP treatment for 3 months achieved significant reductions in 24-h BP.
This effect was seen in patients with ABPM-confirmed RHTN who use CPAP more than 5.8 h/night.
◼ Lozano L, et al, J Hypertens. 2010 ;28:2161-8
Drug therapy in OSAS-related HTN
There is no clear evidence for preference for a specific type of antihypertensive drug and selection should be
guided by the patient’s cardiometabolic profile and associated clinical conditions
◼ Tsioufis et al, J Hypertension 2010
Drug-induced RHTN
Nonsteroidal anti-inflammatory drugs (including cyclo-oxygenase-2 inhibitors)
Sympathomimetics (decongestants, anorectics)
Cocaine, amphetamines, other illicit drugs
Oral contraceptive hormones
Adrenal steroid hormones
Erythropoietin
Cyclosporine and tacrolimus
Licorice (included in some chewing tobacco)
Over-the-counter dietary and herbal supplements (e.g. ginseng, yohimbine,
bitter orange)
Antiangiogenic drugs induced hypertension
De novo HTN or worsening HTN in
association with anti angiogenic drugs varies
between 17-90%
Preferable choice: NO donors
Low interaction potential: RAS blockers, diuretics ,
b-blockers
Use cautiously : CCBs
Contrainticated: verapamil, diltiazem
Prevalence of PA in Patients with RHTN
Calhoun DA, Annu Rev Med 2013; 64: 233-247
(%)
20
17
22
19
7
11
0
5
10
15
20
25
30
BirminghamUSA
SeattleUSA
OsloNorway
PragueCzech Rep.
ShanghaiChina
ThessalonikiGreece
Primary aldosteronism is an underdiagnosed cause of RHTN
Variable Presentation of Primary aldosteronism
• Hypertension
• Unexplained hypokalemia
• Metabolic alkalosis
The presence of PA should be suspected in any patient with the triad of:
Mulatero P et al. J Clin Endocrinol Metab 2004
Normokalemia is more common than hypokalemia
<50% of diagnosed cases were hypokalemic at presentation
Drug therapy and Aldo/PRA ratio
β- blockers
ΑCE-inh
ΑΤ1
α- blockers
ALD
PRAARR
False positive
ALD
PRA
ARR
False negative
PRA, ALDDiuretics
What is his cardiovascular risk?
2018 ESH/ESC Hypertension Guidelines
Classification of hypertension stages according to BP levels, presence of CV risk factors, HMOD, or comorbidities
SCORE CV risk assessment is recommended.
Stratification of total CV risk in categories of low, moderate, high and very high risk
To:
• Achieve BP control over 24 hours
• Protect against Target Organ Damage
• Reduce Mortality
What is the aim of treatment?
To:
• Reduce weight
• Limit salt intake
• Start drug treatment
What is the treatment Strategy?
Effects of BP Lowering (10/5 mmHg SBP/DBP) in Trials with Average Baseline BP in Grade 1 and Average Low-to-Moderate CV Risk
Thomopoulos et al., J Hypertens 2014; 32: 2296
Outcome
Stroke
CHD
Stroke + CHD
CV Death
All-cause Death
Trials
(n)
4
5
4
4
4
Baseline
SBP/DBP
(mmHg)
146/91
145/91
146/91
146/91
146/91
Difference
SBP/DBP
(mmHg)
-7.1/-4.5
-6.5/-4.2
-7.1/-4.5
-7.1/-4.5
-7.1/-4.5
Absolute
Risk Reduction
1000 pts/5 years
(95%CI)
-21 (-26, -1)
-12 (-18, -2)
-34 (-43, -19)
-9 (-14, +1)
-19 (-25, -8)
NNT
5 years
(95% CI)
47 (39, 1301)
86 (55, 531)
29 (23, 54)
110 (72, -2223)
54 (40, 119)
Standardized RR
(95% CI)
0.1 0.2 0.5 1 2 5
Active better Control better
Standardized RR
(95% CI)
0.33 (0.11-0.98)
0.68 (0.48-0.95)
0.51 (0.36-0.75)
0.57 (0.32-1.02)
0.53 (0.35-0.80)
Treatment of grade I HTN low-moderate CV risk◼ No direct evidence from RCT
2018 ESH/ESC Hypertension Guidelines
Thresholds for initiation of BP-lowering treatment less conservative
2018 ESH/ESC Hypertension Guidelines, Summary of Office BP thresholds for treatment
Office BP Thresholds for treatment
Uncontrolled on 2 drugs
Hypertension drug-treatment strategy:Which is the most effective evidence-based treatment strategy to improve BP control?
Ratio of observed to expected incremental blood pressure-lowering effects* of
adding a drug or doubling the dose according to the class of drug (n = 11000, 42
studies)
Wald DS et al., Am J Med 2009; 122: 290
Incr
emen
tal
SB
P r
edu
ctio
n r
ati
o
of
ob
serv
ed t
o e
xp
ecte
d a
dd
itiv
e ef
fect
s
* The expected incremental effect is the incremental blood pressure reduction of the added (or doubled drug), assuming an
additive effect and allowing for the smaller reduction from 1 drug (or dose of 1 drug) given the lower pretreatment blood
pressure because of the other
1.5
1.0
0.5
0.0
Adding a drug from
another class (on average
standard doses)
Doubling dose of same
drug (from standard
dose to twice standard)
1.04
(0.88-1.20)
1.00
(0.76-1.24)
1.16
(0.93-1.39)
0.89
(0.69-1.09)
1.01
(0.90-1.12)
0.19
(0.08-0.30)
0.23
(0.12-0.34)0.20
(0.14-0.26)
0.37
(0.29-0.45)
0.22
(0.19-0.25)
Thiazide Beta-
blocker
ACE-
inhibitor
Calcium channel
blocker
All
classes
Core drug-treatment strategy for uncomplicated hypertension
The core algorithm is also appropriate for most patients with HMOD, cerebrovascular disease, diabetes, or PAD
Treatment
Started on RAS blocker/Amlodipine
41
42
ΑΝΤΑΓΩΝΙΣΤΕΣ ΑΣΒΕΣΤΙΟΥ στην ΑΥΠλεονεκτήματα
1. Υψηλή αποτελεσματικότητα
Ιδίως σε ISH
Υπέρταση εκ κυκλοσπορίνης
Αλατοευαίσθητους-σύνδρομο Raynaud’s-ΧΑΠ-Διαστολική
καρδιακή ανεπάρκεια
2. Επιτυχής συνδυασμός με όλα τα υπόλοιπα αντιυπερτασικά
3. Ίσως υπερτερεί σε άτομα υψηλού κινδύνου για ΑΕΕ
Each class vs all other
D BB CA ACEI ARB RASB
Stroke
CHD
HF
St + CHD
St + CHD + HF
CV Death
All-cause Death
Summary results of the direct comparisons of each class vs all other classes of BP-lowering drugs on seven major outcomes
Thomopoulos, Parati, Zanchetti, J Hypertens 2015; 33: 1321-1341
Chlorthalidone and indapamide have been used in a number of RCTs showing CV benefits,
and these agents are more potent per milligram than hydrochlorothiazide in lowering BP,
with a longer duration of action compared with hydrochlorothiazide and no evidence of a
greater incidence of side effects.
A recent meta-analysis of placebo-controlled : similar effects on CV outcomes of the three
types of diuretics.
……..thiazides, chlorthalidone, and indapamide can all be considered suitable
antihypertensive agents.
Treatment of HTN: Which diuretic
ESC/ESH guidelines 2018
Treatment
Started on RAS blocker/Amlodipine
Follow up after 4 weeks months:
• office BP 130/85 mmHg
Does the patient receive regularly the antihypertensive
medications? (medication adherence)
Can we optimize the antihypertensive therapy?
For every 100
prescriptions written:
30%–50% never makeit to the pharmacy
34%–52% are filledbut never picked up
70%–75% are nottaken as prescribed
15-20% are refiled as prescribed
The importance of a collaborative approach
PhysicianNurse
( building a personal connection to identify a
patient’s treatment concerns)
Pharmacist(Establishing themselves as a
primary educator for the patient)
Specialist(simplifying
optimal therapy)
Each profession should value the unique role that others can play in
enhancing patient adherence
Agenda
◼ Office BP or out of office BP
◼ How to measure BP correctly
◼ How to manage Hypertension in the very elderly
◼ Do beta blockers have any role in the HTN management
◼ How to manage Resistant hypertension
◼ Do antihypertensive drugs increase the risk of cancer
◼ Should we use RDN for the routine treatment of HTN
Limited Available data
◼ How to manage Hypertension in the very elderly
How old would you be if you didn’t know how old you are?Satchel Paige
Management of Hypertension in the very elderly
80+ years
The most « hypertensive » population (prevalence of HTN over 80 yrs >75%)
The most growing population (5% in 2015, 10% in 2040 will be over 80 yrs)
The most heterogeneous population
Young hyperadrenergichypertensive patient
Obese metabolichypertensive patient
Elderly hypertensivevascular patient
Different hypertensive phenotypes
Many comorbidities- CKD,CAD, StrokeToo many drugs, inappropriate useIncreased number of side effects Increased hospitalizationsIncreased fraility
80+: 5.7% (3.8 M)
35% (1.3 M) significant
loss of autonomy
50% (650,000)
Living in NHs
50% (650,000)
At home with
daily assistance
Population in France: 66 M
>4 chronic diseases
>8 different medications/day
0% have the inclusion criteria of HYVET and
SPRINT
65% (2.5 M): preserved
autonomy for activities
of daily living (ADL)
and often good
functional status
Approx. 30-50% have the
inclusion criteria for HYVET and
SPRINT
Presenting in Athens Meeting by A.Benetos
Who is frail?
2018 ESC/ESH Hypertension Guidelines
Williams, Mancia et al., J Hypertens 2018;36:1953-2041 and Eur Heart J 2018;39:3021-3104
Office BP treatment target range
Age18-65 years
Age>65-79 years*
Age≥ 80 years*
IA IA IA
• First SBP <140 mmHg• Aim for SBP 130 mmHg or
lower if tolerated• DBP <80-70 mmHg• Do not go <120/70 mmHg
• First SBP <140 mmHg• Aim for SBP 130 mmHg
• DBP <80-70 mmHg• Do not go <130/70 mmHg
• First SBP <140 mmHg• Aim for SBP 130 mmHg
• DBP <80-70 mmHg• Do not go <130/70 mmHg
* Consider frailty/independence/tolerability of treatment
77
‘PRESERVED
FUNCTION’
‘LOSS OF
FUNCTION/PRESERVE
D AUTONOMY’
(FOR THE ADL)
-Therapeutic approach
similar to younger
adults with treatment
goal: SBP 130-140
mmHg
-Start with
monotherapy and
titrate antihypertensive
medication cautiously
-Always check for
orthostatic
hypotension
Tailor
antihypertensive
strategy after a
detailed geriatric
assessment.
‘LOSS OF AUTONOMY’
(FOR THE ADL)
-Revision of the
prescription
-If BP lowering it is
considered, SBP goal
140-150 mmHg ;
-Under treatment: SBP <
130 mmHg or orthostatic
hypotension: Consider
reducing antihypertensive
treatment.
-Correct other factors
and medications
decreasing BP
Moderately
altered
functional
status
Significantly
altered
functional
status
ADAPTING ANTIHYPERTENSIVE STRATEGIES ACCORDING TO
THE PROFILE OF THE ‘FRAILTY/FUNCTION/AUTONOMY’ STATUS
Benetos A, Petrovic M, Strandberg T, Circ. Res. 2019, 124: 1045-1060
Magkas, Tsioufis et al, J Clin Hypertens (Greenwich). 2019
Jordan J et al. J Hypertens 2019; Epub
↓ Supine blood pressure
↓ Nocturnal sodium excretion
↓ Orthostatic hypotension in morning
◼ How to manage Resistant hypertension
Different but arbitrary Terminology for the same clinical problem
◼ Resistant Hypertension (Treatment Resistant Hypertension) (5-30% in the overall hypertensive population)
◼ Apparent Treatment Resistant Hypertension (2-5%)
◼ Resistant Controlled Hypertension (21%)
◼ Refractory Hypertension (5% of the Resistant Hypertension)
…but consensus about the adverse prognosis
Patterns of RHTN and CV events1911 treated hypertensive patients for a mean period of 3.9 years follow up
6.4 events
9.1events
13.2 events
18.1 events
Tsioufis C, et al. J Hypertens. 2013
Resistant hypertensionRecommendations Class Level
It is recommended that hypertension be defined as resistant to treatment (i.e.
resistant hypertension) when:
• Optimal doses (or best-tolerated doses) of an appropriate therapeutic strategy,
which should include a diuretic (typically an ACE inhibitor or an ARB with a CCB
and a thiazide/thiazide-type diuretic), fails to lower clinic SBP and DBP values to <
140 mmHg and/or 90 mmHg, respectively; and
• The inadequate control of BP has been confirmed by ABPM or HBPM; and
• After exclusion of various causes of pseudo-resistant hypertension (especially
poor medication adherence) and secondary hypertension.
I C
2018 ESC/ESH Hypertension Guidelines
Core drug-treatment strategy for uncomplicated hypertension
The core algorithm is also appropriate for most patients with HMOD, cerebrovascular disease, diabetes, or PAD
Subgroup analysis comparing the effects of mineralocorticoid receptorantagonists on achieved blood pressure difference between resistanthypertension and nonresistant hypertension trials
Bazoukis, Thomopoulos, Tsioufis. J Hypertens. 2018 May;36(5):987-994
Although the rate of BP control was similarbetween the 2 tested drugs, spironolactone is preferable as a fourth drug considering the dosage facilities and higher impact in some ABPM secondary end points.
◼ hould we use RDN for the routine treatment of HTN
Device-based therapies for hypertension
Recommendation Class Level
Use of device-based therapies is not recommended for the routine
treatment of hypertension, unless in the context of clinical studies and
RCTs, until further evidence regarding their safety and efficacy
becomes available.
III B
RDN for HTN management: Back on track
RDN: Efficacy to lower BP
-9
-1,6
-14
-12
-10
-8
-6
-4
-2
0
Systolic
RDN Sham
152
RDN(N=36)
Sham(N=36)
ON Med6 months24-h systolic BP
-12.7 to -5.3p<0.0001
-5.2 to 2.0p=0.365
(-12.5 to -2.3)p=0.0051
-5,5
-0,5
-14
-12
-10
-8
-6
-4
-2
0
Systolic
RDN Sham
-9.1 to -2.0p=0.003
-3.9 to 2.9p=0.76
RDN(N=35)
Sham(N=36)
OFF Med3 months24-h systolic BP
(-9.9 to -0.2)p=0.04
-8,5
-2,2
-14
-12
-10
-8
-6
-4
-2
0
Systolic
RDN Sham
RDN(N=74)
Sham(N=72)
SOLO2 monthsDaytime systolic BP
-10.6 to -6.3
-4.5 to 0.2
(-9.4 to -3.1)p<0.001
151150 150 153152
-6.3 -5.0-7.4
Schmieder RE ESH 2018
Change in Ambulatory BP in RADIANCE SOLO, SPYRAL HTN OFF MED and SPYRAL HTN ON MED
SPYRAL HTN – OFF MED
24-hr Systolic Blood Pressure from Baseline to 3 Months
RDN
130
140
150
160
170
1am
2am
3am
4am
5am
6am
7am
8am
9am
10a
m
11a
m
12p
m
1p
m
2p
m
3p
m
4p
m
5p
m
6p
m
7p
m
8p
m
9p
m
10p
m
11p
m
12a
m
Systo
lic
Blo
od
Pre
ssu
re (
mm
Hg
)
Sham Control
130
140
150
160
170
1am
2am
3am
4am
5am
6am
7am
8am
9am
10a
m
11a
m
12p
m
1p
m
2p
m
3p
m
4p
m
5p
m
6p
m
7p
m
8p
m
9p
m
10p
m
11p
m
12a
m
3 Months
Baseline
3 Months
Baseline
Graphs based on actual clock times. Similar results were observed when 24-hour BP patterns were normalized to patient reported time of waking.
Kario K, et al. Circulation 2018ss
▪ RDN: ‘’always on” effect
Renal Denervation (N=74)
Sham Procedure (N=72)
% Patients with
≥ 5 mm Hg Decrease
Renal Denervation: 66%
Sham Procedure: 33%
P<0.001
66%
33%
Unmet Needs –I. Identification of Responders
Azizi M, Lancet 2018
Unmet Needs –II. Real time feedback
Mapping Ablation Verification
Four pivotal trials in HTN are underway◼ SPYRAL OFF-MED PIVOTAL
◼ RADIANCE SOLO II
◼ SPYRAL ON-MED PIVOTAL
◼ REQUIRE PIVOTAL
No drugs
On drugs
Larger trials beyond HTN is under development